A G-protein coupled receptor (CX5) expressed in human promyelocytic leukemic cell line (HL60) was discovered in 1993. This was later identified as type II Cannabinoid receptor (Munro et al. Nature (1993), 365, 61-65). CB2 receptors are found to be expressed predominantly in immune cells. When activated they modulate immune cell migration and cytokine release outside and within the brain (Pertwee et al. Handb. Exp. Pharmacol. (2005), 168, 1-51). CB2 activation affects a host of immune responses from inflammation to neuroprotection (Cabral at al. Handb. Exp. Pharmacol. (2005), 168, 385-423). The activation of CB2 receptors is reported to have analgesic effect in many animal models of pain from acute pain to neuropathic pain (Anand et al. Pain. (2009), 138, 667-680).
Since CB2 is an attractive therapeutic target for pain management and immune system modulation without overt psycho activity and substance abuse possibility, its presumed absence in the CNS was reviewed by many researchers. The findings of these recent investigations support the presence of CB2 receptors in CNS. The CB2 mRNA and protein have been found in microglia (Beltramo et al. Eur. J. Neurosci. (2006), 23, 1530-1538; Carlisle et al. Int. Immuno pharmacol. (2002), 2, 69-82; Klegeris at al. Br. J. Pharmacol. (2003), 139, 775-786; Maresz et al., Nat. Med. (2007), 13, 492-497; Walter et al. J. Neurosci. (2003), 23, 1398-1405). The expression levels of CB2 are proportional to the activation extent of microglia (Cabral et al., Br. J. Pharmacol. (2008), 153, 240-251; Pietr et al. FEBS Lett. (2009), 583, 2071-2076; Stella et al. Glia. (2004), 48, 267-277). Microglial migration and their infiltration into brain areas with active neuroinflammation and degeneration is modulated by CB2. In healthy brain microglia does not express CB2 but they do in Alzheimer's brain tissue in the neuritic-plaque associated microglia (Benito et al. J Neurosci. (2003), 23, 11136-11141). In the neuropathic pain models CB2 mRNA is found to increase in association with activated microglia in the spinal cord (Zhang at al. Eur. J. Neurosci. (2003), 17, 2750-2754). Similarly in amyotrophic lateral sclerosis and multiple sclerosis, CB2 microglial expression increases in spinal cord (Yiangou et al. BMC. Neurol. (2006), 6, 12).
As reported earlier highest CB2 receptor distribution is also known in macrophages, CD4 T cells, CD8 T cells, B cells, natural killer cells, monocytes, and polymorphonuclear neutrophils (Dittel B N. et al. BJP. (2008), 153, (2), 271-276; Maresz K. et al. Nature Medicine. (2007), 13, 492-497). Similarly CB2 receptor presence is also known in other brain areas like thalamus, straitum, hippocampus. Peripheral neurons, nociceptive neurons and sensory neurons also are known to express CB2 receptors.
Apart from the relevance of CB2 in the area of pain management, this receptor is also known to be involved in other functions. For example CB2 receptor is expressed in the bone cells and is reported to have anabolic effect on bones (Ofek et al. PNAS. (2006), 103, 696-701). Presence of CB2 is also reported in the enteric nervous system, (Duncan M Mouihate et al, Am. J. Physiol. Gastrointest. Liver Physiol. 295, G78-G87). Similar anabolic effect is also reported through CB2 receptor mediation in neurogenesis (Molina-Holgado et al. Eur. J. Neurosci. (2007), 25, 629-634 & Palazuelos J. et al. FASEB J. (2006), 20, 2405-2407).
Role of CB1 in pain management is also well known. This receptor is known to exist majorly in the central nervous system. To a minor extent, CB1 is also reported to exist in the periphery (Pharmacology, Biochemistry and Behavior 90 (2008) 501-511). Therefore, along with compounds that are CB2 selective modulators, dual modulators working through CB1 and CB2 are also targeted.
WO 2002/042248, WO 2010/096371, WO 2010/133973, WO 2006/129178, WO 2010/084767, WO 2009/053799, WO 2008/115672, WO 2008/027812, WO 2007/102059, WO 2007/091950 and WO 2002/42248 applications disclose compounds related to cannabinoid receptors for the treatment of various diseases mediated by cannabinoid receptors. Also, Bioorganic Medicinal Chemistry, (2011), 19, 939-950, discloses the compounds related to cannabinoid receptors.